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Purpose: To assess for risk factors for retinal vein occlusion (RVO) among participants in the National Institutes of Health All of Us database, particularly social risk factors that have not been well studied, including substance use. Design: Retrospective, case-control study. Participants: Data were extracted for 380 adult participants with branch retinal vein occlusion (BRVO), 311 adult participants with central retinal vein occlusion (CRVO), and 1520 controls sampled among 311 640 adult participants in the All of Us database. Methods: Data were extracted regarding demographics, comorbidities, income, housing, insurance, and substance use. Opioid use was defined by relevant diagnosis and prescription codes, with prescription use > 30 days. Controls were sampled at a 4:1 control to case ratio from a pool of individuals aged > 18 years without a diagnosis of RVO and proportionally matched to the demographic distribution of the 2019 U.S. census. Multivariable logistic regression identified medical and social determinants significantly associated with BRVO or CRVO. Statistical significance was defined as P < 0.05. Main Outcome Measure: Development of BRVO or CRVO based on diagnosis codes. Results: Among patients with BRVO, the mean (standard deviation) age was 70.1 (10.5) years. The majority (53.7%) were female. Cases were diverse; 23.7% identified as Black, and 18.4% identified as Hispanic or Latino. Medical risk factors including glaucoma (odds ratio [OR], 3.29; 95% confidence interval [CI], 2.22–4.90; P < 0.001), hypertension (OR, 2.15; 95% CI, 1.49–3.11; P < 0.001), and diabetes mellitus (OR, 1.68; 95% CI, 1.18–2.38; P = 0.004) were re-demonstrated to be associated with BRVO. Black race (OR, 2.64; 95% CI, 1.22–6.05; P = 0.017) was found to be associated with increased risk of BRVO. Past marijuana use (OR, 0.68; 95% CI, 0.50–0.92; P = 0.013) was associated with decreased risk of BRVO; however, opioid use (OR, 1.98; 95% CI, 1.41–2.78; P < 0.001) was associated with a significantly increased risk of BRVO. Similar associations were found for CRVO. Conclusions: Understanding RVO risk factors is important for primary prevention and improvement in visual outcomes. This study capitalizes on the diversity and scale of a novel nationwide database to elucidate a previously uncharacterized association between RVO and opioid use.

Intravitreal administration for human adeno-associated vector (AAV) delivery is easier and less traumatic to ocular tissues than subretinal injection, but it gives limited retinal transduction. AAV vectors are large (about 4,000 kDa) compared with most intraocular drugs, such as ranibizumab (48 kDa), and the large size impedes diffusion to reach the retina from the usual injection site in the anterior/mid-vitreous. Intuitively, a preferred placement for the vector would be deep in the vitreous near the retina, which we term “para-retinal” delivery. We explored the consequences of para-retinal intravitreal delivery in the rabbit eye and in non-human primate (NHP) eye. 1 h after para-retinal administration in the rabbit eye, the vector concentration near the retina remained four times greater than in the anterior vitreous, indicating limited vector diffusion through the gelatinous vitreous matrix. In NHP, para-retinal placement showed greater transduction in the fovea than vector applied in the mid-vitreous. More efficient retinal delivery translates to using lower vector doses, with reduced risk of ocular inflammatory exposure. These results indicate that para-retinal delivery yields more effective vector concentration near the retina, thereby increasing the potential for better retinal transduction in human clinical application., Graphical Abstract, The authors explored an alternate approach to standard intravitreal administration called “para-retinal” delivery where AAV vectors were placed deep into the vitreous near the retina surface. This modification increased vector concentration in the posterior vitreous in rabbit eyes, minimized vector losses, and enhanced foveal transgene expression in NHP eyes.

Purpose: To describe a unique case of LASIK flap fungal keratitis confirmed by next generation sequencing. Observations: A 56-year-old female presented with refractory keratitis involving her LASIK flap 21 years after surgery. Confocal was positive for filamentous structures. The patient underwent immediate flap amputation followed by topical antifungal treatment. Corneal culture was positive for Acremonium sp. Metagenomic deep sequencing confirmed Acremonium as the primary source of infection and also identified Fusarium as a likely contributor of a mixed fungal infection. Sequencing also identified hay as the likely source of the infection. Treatment resulted in eradication of the infection. The patient's final best corrected visual acuity was 20/30 with rigid contact lens overrefraction. Conclusions: Metagenomic deep sequencing is a novel diagnostic tool that is increasingly being utilized for diagnosis of refractory keratitis. This case demonstrates the diagnostic potential of deep sequencing for identifying post-LASIK keratitis and reinforces the utility of LASIK flap amputation in the setting of tectonic flap instability due to keratolysis. Importance: This case highlights several important clinical points for treating LASIK flap keratitis and highlights the emerging role metagenomic sequencing has in the diagnosis of infectious keratitis. This is first known case using next generation sequencing to diagnose a post-LASIK infectious keratitis.

Summary: Background: WHO promotes the SAFE strategy for the elimination of trachoma as a public health programme, which promotes surgery for trichiasis (ie, the S component), antibiotics to clear the ocular strains of chlamydia that cause trachoma (the A component), facial cleanliness to prevent transmission of secretions (the F component), and environmental improvements to provide water for washing and sanitation facilities (the E component). However, little evidence is available from randomised trials to support the efficacy of interventions targeting the F and E components of the strategy. We aimed to determine whether an integrated water, sanitation, and hygiene (WASH) intervention prevents the transmission of trachoma. Methods: The WASH Upgrades for Health in Amhara (WUHA) was a two-arm, parallel-group, cluster-randomised trial in 40 rural communities in Wag Hemra Zone (Amhara Region, Ethiopia) that had been treated with 7 years of annual mass azithromycin distributions. The randomisation unit was the school catchment area. All households within a 1·5 km radius of a potential water point within the catchment area (as determined by the investigators) were eligible for inclusion. Clusters were randomly assigned (at a 1:1 ratio) to receive a WASH intervention either immediately (intervention) or delayed until the conclusion of the trial (control), in the absence of concurrent antibiotic distributions. Given the nature of the intervention, participants and field workers could not be masked, but laboratory personnel were masked to treatment allocation. The WASH intervention consisted of both hygiene infrastructure improvements (namely, construction of a community water point) and hygiene promotion by government, school, and community leaders, which were implemented at the household, school, and community levels. Hygiene promotion focused on two simple messages: to use soap and water to wash your or your child's face, and to always use a latrine for defecation. The primary outcome was the cluster-level prevalence of ocular chlamydia, measured annually using conjunctival swabs in a random sample of children aged 0–5 years from each cluster at 12, 24, and 36 month timepoints. Analyses were done in an intention-to-treat manner. This trial is ongoing and is registered at ClinicalTrials.gov, NCT02754583. Findings: Between Nov 9, 2015, and March 5, 2019, 40 of 44 clusters assessed for eligibility were enrolled and randomly allocated to the trial groups (20 clusters each, with 7636 people from 1751 households in the intervention group and 9821 people from 2211 households in the control group at baseline). At baseline, ocular chlamydia prevalence among children aged 0–5 years was 11% (95% CI 6 to 16) in the WASH group and 11% (5 to 18) in the control group. At month 36, ocular chlamydia prevalence had increased in both groups, to 32% (24 to 41) in the WASH group and 31% (21 to 41) in the control group (risk difference across three annual monitoring visits, after adjustment for prevalence at baseline: 3·7 percentage points; 95% CI –4·9 to 12·4; p=0·40). No adverse events were reported in either group. Interpretation: An integrated WASH intervention addressing the F and E components of the SAFE strategy did not prevent an increase in prevalence of ocular chlamydia following cessation of antibiotics in an area with hyperendemic trachoma. The impact of WASH in the presence of annual mass azithromycin distributions is currently being studied in a follow-up trial of the 40 study clusters. Continued antibiotic distributions will probably be important in areas with persistent trachoma. Funding: National Institutes of Health—National Eye Institute. Translation: For the Amharic translation of the abstract see Supplementary Materials section.

Author(s): Mekonnen, Zesemayat K; Everett, Lesley A; Hetts, Steven W; Afshar, Armin R | Abstract: PurposeTo describe acute and chronic retinal ischemic changes following an internal carotid artery pseudoaneurysm stenting procedure, and to review current evidence for risk factors and management of post-procedural retinal ischemic events.ObservationA 50-year-old man presented with a 3-month history of pulsatile tinnitus, headache, and intermittent blurry vision. A CT angiogram of head and neck showed bilateral cervicopetrous internal carotid artery (ICA) pseudoaneurysms. The patient underwent successful repair with angioplasty and stenting of the flow-limiting high-grade (g95%) stenosis of his left high cervical ICA. On post-operative day 1, the patient reported monocular vision loss with a large central scotoma. He was found to have a central macular area of retinal whitening and multiple areas of perivascular retinal whitening on exam, concerning for retinal artery occlusions secondary to peri-procedural emboli. Dual antiplatelet therapy was started and a stroke evaluation was performed. Two months later, his visual acuity in the affected eye was counting fingers and his left eye fundus examination was notable for multiple areas of scattered hemorrhages, microaneurysms, and retinal exudates in the distribution of prior retinal ischemia. OCT imaging revealed atrophic changes in the left macula. Subsequently, the patient completed stage-2 repair of the left ICA pseudoaneurysm followed by uncomplicated repair of the right ICA. Four months later, his left eye visual acuity and retinal findings remained stable.Conclusions and importancePost-procedure retinal emboli and ischemia are important, vision threatening possible ocular complications for patients undergoing carotid vascular and endovascular procedures.

Purpose Mantle cell lymphoma is a rare aggressive subtype of non-Hodgkins B cell lymphoma. It typically presents with asymptomatic monoclonal lymphocytosis, lymphadenopathy or bulky extranodal disease. Mantle cell lymphoma rarely affects the central nervous system. We present two cases in which vision loss was the initial symptom of central nervous system involvement by the malignancy. Observations Both patients initially received high dose intravenous steroids with notable improvement in their vision. Conclusions and importance Early detection and management of optic nerve infiltration by mantle cell lymphoma is essential as it improves visual outcomes and enables prompt management of the patient's systemic disease.

Fourty-seven-year-old woman with 5-year history of progressive decreased left eye vision. Optical coherence tomography showed optic nerve atrophy (left > right) and brain MRI revealed T2 hyperintense signal along the course of left optic radiations. We present a case of a trans-synaptic degeneration of the optic radiation in a patient with confirmed optic atrophy. Trans-synaptic degeneration of the optic radiation without associated infarct or inflammatory disease has not been reported before in patients with optic atrophy.

Purpose The most common treatment protocol for whole-brain radiation therapy (WBRT) is 30 Gy in 10 fractions. This regimen entails a low risk of radiation retinopathy, with fewer than a dozen reported cases. We describe a case of radiation retinopathy that was confined to the superior retinae. These regions were the only portions of the eyes that were included in the treatment field. Methods and Materials Observational case report consisting of clinical examination, review of radiation treatment planning and implementation, computerized visual field testing, and fundus photography. Results A 36-year-old man with metastatic lung adenocarcinoma developed radiation retinopathy 16 months after WBRT to 30 Gy in 10 fractions. The retinopathy was largely confined to the superior halves of the retinae. There was corresponding geographic inferior visual field loss in both eyes. Review of the patient's treatment protocol revealed that the superior retinae received a substantial radiation dose, approaching 30 Gy, whereas the inferior retinae were essentially outside the treatment field. Conclusions In this patient, the correlation between the treatment field and the resulting local development of radiation retinopathy demonstrated unequivocally that the relatively low dose used in routine WBRT (ie, 30 Gy in 10 fractions) can induce radiation retinopathy.

Purpose To investigate ON-pathway versus OFF-pathway dysfunction in glaucoma using handheld electroretinography (ERG) with a temporally modulated sinusoidal flicker stimulus. Design Cross-sectional study. Participants Fifty-nine participants accounting for 104 eyes, comprised of 19 control eyes, 26 glaucoma suspect eyes, and 59 glaucoma eyes. Methods Participants underwent portable ERG testing, which included the photopic flash, photopic flicker, photopic negative response stimulus, ON-OFF stimulus, and a custom-written sinusoidal flicker stimulus that was modulated from 50 to 0.3 Hz. Main Outcome and Measures The ERG response amplitudes were measured by the handheld ERG. For the custom-written sinusoidal flicker stimulus, we derived and compared the log10 first harmonic frequency response amplitudes. Patient discomfort and fatigue after ERG testing were rated on a scale from 1 to 5 Results Baseline demographics were not significantly different between groups, except for ocular characteristics. Analysis was performed adjusting for participant age, sex, race, and dilation status, and the sinusoidal frequency responses were stratified at 10 Hz because higher frequencies are associated with the OFF-pathway, whereas lower frequencies are associated with the ON-pathway. After stratification, glaucoma eyes showed an adjusted decrease of 32.1% at frequencies of more than 10 Hz (95% confidence interval [CI], −51.8% to −4.1%; P = 0.03). For 10 Hz stimulus frequencies or less, an adjusted 11.5% reduction was found (95% CI, −39.5% to 29.1%; P = 0.50). Glaucoma suspect eyes did show a decreased response, but this was not significant at either frequency range. When comparing handheld ERG with traditional visual field assessments, participants found the handheld ERG to result in much less discomfort and fatigue. Conclusions Our finding that glaucoma participants showed greater decreases in ERG response at higher frequencies supports the hypothesis that the OFF-pathway may be more vulnerable in human glaucoma. Using a handheld ERG device with a sinusoidal flicker stimulus may provide an objective assessment of visual function in glaucoma.

Background In the absence of accessible, good quality eye health services and inclusive environments, vision loss can impact individuals, households and communities in many ways, including through increased poverty, reduced quality of life and reduced employment. We aimed to estimate the annual potential productivity losses associated with reduced employment due to blindness and moderate and severe vision impairment (MSVI) at a regional and global level. Methods We constructed a model using the most recent economic, demographic (2018) and prevalence (2020) data. Calculations were limited to the working age population (15–64 years) and presented in 2018 US Dollars purchasing power parity (ppp). Two separate models, using Gross Domestic Product (GDP) and Gross National Income (GNI), were calculated to maximise comparability with previous estimates. Findings We found that 160.7 million people with MSVI or blindness were within the working age and estimated that the overall relative reduction in employment by people with vision loss was 30.2%. Globally, using GDP we estimated that the annual cost of potential productivity losses of MSVI and blindness was $410.7 billion ppp (range $322.1 - $518.7 billion), or 0.3% of GDP. Using GNI, overall productivity losses were estimated at $408.5 billion ppp (range $320.4 - $515.9 billion), 0.5% lower than estimates using GDP. Interpretation These findings support the view that blindness and MSVI are associated with a large economic impact worldwide. Reducing and preventing vision loss and developing and implementing strategies to help visually impaired people to find and keep employment may result in significant productivity gains Funding MJB is supported by the Wellcome Trust (207472/Z/17/Z). JR's appointment at the University of Auckland is funded by the Buchanan Charitable Foundation, New Zealand. The Lancet Global Health Commission on Global Eye Health was supported by grants from The Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity (GR001061), NIHR Moorfields Biomedical Research Centre, The Wellcome Trust, Sightsavers, The Fred Hollows Foundation, The SEVA Foundation, The British Council for the Prevention of Blindness and Christian Blind Mission. The funders had no role in the design, conduct, data analysis of the study, or writing of the manuscript.

Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Despite its high prevalence, the factors contributing to glaucoma progression are currently not well characterized. Glia-driven neuroinflammation and mitochondrial dysfunction play critical roles in glaucomatous neurodegeneration. Here, we demonstrated that elevated intraocular pressure (IOP) significantly decreased apolipoprotein A-I binding protein (AIBP; gene name Apoa1bp) in retinal ganglion cells (RGCs), but resulted in upregulation of TLR4 and IL-1β expression in Müller glia endfeet. Apoa1bp−/− mice had impaired visual function and Müller glia characterized by upregulated TLR4 activity, impaired mitochondrial network and function, increased oxidative stress and induced inflammatory responses. We also found that AIBP deficiency compromised mitochondrial network and function in RGCs and exacerbated RGC vulnerability to elevated IOP. Administration of recombinant AIBP prevented RGC death and inhibited inflammatory responses and cytokine production in Müller glia in vivo. These findings indicate that AIBP protects RGCs against glia-driven neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration and suggest that recombinant AIBP may be a potential therapeutic agent for glaucoma., Graphical abstract Image 1, Highlights • AIBP loss induces glia-driven neuroinflammation and triggers mitochondrial dysfunction in glaucomatous neurodegeneration. • AIBP regulates mechanisms protecting against mitochondrial dysfunction, Müller glia activation and RGC death. • Administration of recombinant AIBP deactivates Müller glia and protects RGCs and has therapeutic potential for glaucoma.

Purpose To report a case of visual recovery and vascular reperfusion after vaso-occlusive retinopathy from anti-phospholipid syndrome associated with systemic lupus erythematosus. Observations A 15-year-old boy with a known diagnosis of systemic lupus erythematosus and a clinically significant anti-phospholipid panel presented with sudden vision loss in the left eye. Examination and ocular imaging revealed signs of vaso-occlusive retinopathy. The patient was immediately started on high dose intravenous steroids, followed by mycophenolate mofetil. He remained on aspirin. After showing no improvement in retinal arteriole and capillary perfusion he was started on therapeutic anti-coagulation with enoxaparin. He regained 20/20 vision. Intravenous fluorescein angiography demonstrated reperfusion of retinal arterioles. Optical coherence tomography angiography showed return of flow in the capillary networks. Conclusions We present a case of vaso-occlusive retinopathy in a patient with known systemic lupus erythematosus and a clinically significant anti-phospholipid panel, thus meeting criteria for anti-phospholipid syndrome. He was treated with intravenous methylprednisolone, mycophenolate motefil, aspirin, and enoxaparin. The patient not only had great recovery of visual acuity, but also demonstrated reperfusion of arterioles and reconstitution of flow in the retinal capillary network. These findings suggest that the vaso-occlusive disease is reversible if the diagnosis is made promptly and intensive therapy is initiated. Importance Currently there are no reported cases of vaso-occlusive retinopathy from APLS and SLE with visual recovery, reperfusion, and return of capillary flow.

Purpose To describe the first series of six young uveal melanoma (UM) patients with oral isotretinoin and/or topical retinoid therapy prior to diagnosis. Observations The case series is based on clinical observations at our UM quaternary referral center. Six UM patient cases are reported, ages 16–44 years old. All had been using either oral (isotretinoin) and/or topical (tretinoin or tazarotene) retinoid treatment (3 months–~10 years) prior to or at the time of diagnosis (3 of 6 cases). All patients had ocular complaints on presentation, and the onset of certain symptoms corresponded with the course of retinoids. Other potential risk factors or relevant history included Caucasian background, cone-rod dystrophy and active smoker status (Case 2), family history of UM and pregnancy at time of diagnosis (Case 3), past smoking and possible secondary Chernobyl exposure as a baby (Case 5). All patients were treated with proton beam radiotherapy and currently have no sign of recurrent or metastatic disease. Conclusions and importance Retinoid therapy has been linked to various benign and/or reversible effects on the anterior and posterior eye, though pathophysiology remains not well understood. Uveal melanoma (UM) is a rare cancer diagnosis in young adults. We report here the first case series of young UM patients with a history of retinoid use and ocular complaints. No causal link is claimed and further systematic epidemiologic and biologic study of retinoid therapy and ocular impact may provide additional relevant data, particularly in young ocular melanoma patients.

Retinal ganglion cell (RGC) degeneration is the root cause for vision loss in glaucoma as well as in other forms of optic neuropathy. A variety of studies have implicated abnormal mitochondrial quality control (MQC) as contributing to RGC damage and degeneration in optic neuropathies. The ability to differentiate human pluripotent stem cells (hPSCs) into RGCs provides an opportunity to study RGC MQC in great detail. Degradation of damaged mitochondria is a critical step of MQC, and here we have used hPSC-derived RGCs (hRGCs) to analyze how altered mitochondrial degradation pathways in hRGCs affect their survival. Using pharmacological methods, we have investigated the role of the proteasomal and endo-lysosomal pathways in degrading damaged mitochondria in hRGCs and their precursor stem cells. We found that upon mitochondrial damage induced by the proton uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP), hRGCs more efficiently degraded mitochondria than did their precursor stem cells. We further identified that for degrading damaged mitochondria, stem cells predominantly use the ubiquitine-proteasome system (UPS) while hRGCs use the endo-lysosomal pathway. UPS inhibition causes apoptosis and cell death in stem cells, while hRGC viability is dependent on the endo-lysosomal pathway but not on the UPS pathway. These findings suggest that manipulation of the endo-lysosomal pathway could be therapeutically relevant for RGC protection in treating optic neuropathies associated with mitophagy defects. Endo-lysosome dependent cell survival is also conserved in other human neurons as we found that differentiated human cerebral cortical neurons also degenerated upon endo-lysosomal inhibition but not with proteasome inhibition., Graphical abstract The above graphical abstract represents a summary of the data presented in this work. Our data shows human pluripotent stem cells (hPSCs) predominantly use the ubiquitin-proteasome system (UPS) for maintaining mitochondrial homeostasis. However, during the course of differentiation to human retinal ganglion cells (hRGCs), cellular preference for maintaining mitochondrial homeostasis shifts towards the endo-lysosomal pathway, which becomes essential for hRGC survival.Image 1, Highlights • Human retinal ganglion cells (hRGCs) degrade damaged mitochondria more efficiently than the origin stem cells. • Human stem cells rely on the ubiquitin proteasome system (UPS) for damaged mitochondrial clearance and survival. • hRGCs rely on the endo-lysosomal pathway for mitochondrial clearance and survival. • Unlike stem cells, proteasomal inhibition did not cause severe cell death for hRGCs. • Transition from the UPS to endo-lysosomal pathway during differentiation was also observed for cerebral cortical neurons.

Summary: Changes in dendritic morphology in response to activity have long been thought to be a critical component of how neural circuits develop to properly encode sensory information. Ventral-preferring direction-selective ganglion cells (vDSGCs) have asymmetric dendrites oriented along their preferred direction, and this has been hypothesized to play a critical role in their tuning. Here we report the surprising result that visual experience is critical for the alignment of vDSGC dendrites to their preferred direction. Interestingly, vDSGCs in dark-reared mice lose their inhibition-independent dendritic contribution to direction-selective tuning while maintaining asymmetric inhibitory input. These data indicate that different mechanisms of a cell’s computational abilities can be constructed over development through divergent mechanisms.

Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from the short-chain dehydrogenase/reductase and aldehyde dehydrogenase gene families. Serum retinol binding-protein delivers all-trans-retinol (vitamin A) from blood to cells through two membrane receptors, Stra6 and Rbpr2. Stra6 and Rbpr2 convey retinol to cellular retinol binding-protein type 1 (Crbp1). Holo-Crbp1 delivers retinol to lecithin: retinol acyl transferase (Lrat) for esterification and storage. Lrat channels retinol directly into its active site from holo-Crbp1 by protein-protein interaction. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through regulating esterification vs ester hydrolysis. Multiple retinol dehydrogenases (Rdh1, Rdh10, Dhrs9, Rdhe2, Rdhe2s) channel retinol from holo-Crbp1 to generate retinal for ATRA biosynthesis. β-Carotene oxidase type 1 generates retinal from carotenoids, delivered by the scavenger receptor-B1. Retinal reductases (Dhrs3, Dhrs4, Rdh11) reduce retinal into retinol, thereby restraining ATRA biosynthesis. Retinal dehydrogenases (Raldh1, 2, 3) dehydrogenate retinal irreversibly into ATRA. ATRA regulates its own concentrations by inducing Lrat and ATRA degradative enzymes. ATRA exhibits hormesis. Its effects relate to its concentration as an inverted J-shaped curve, transitioning from beneficial in the "goldilocks" zone to toxicity, as concentrations increase. Hormesis has distorted understanding physiological effects of ATRA post-nataly using chow-diet fed, ATRA-dosed animal models. Cancer, immune deficiency and metabolic abnormalities result from mutations and/or insufficiency in Crbp1 and retinoid metabolizing enzymes.

Purpose: To report a case of metastatic intraocular medulloepithelioma successfully treated with neoadjuvant chemotherapy, superficial parotidectomy, and enucleation. Observations: A 5-year-old male with history of cataract surgery, glaucoma drainage device, endocyclophotocoagulation, scleral patch grafting, and chronic posterior “inflammation” in a blind left eye presented with a rapidly enlarging painful mass under the left upper eyelid. Biopsy of the conjunctival mass and fine needle aspiration of an enlarged preauricular lymph node revealed medulloepithelioma, which was also seen in the left parotid gland on positron emission tomography (PET) scan. The patient's father refused exenteration, so the patient received 3 cycles of vincristine, cisplatin, cyclophosphamide, and etoposide per a retinoblastoma protocol. Repeat magnetic resonance imaging (MRI) showed regression of ocular extension, and an enucleation was performed, histologically confirming the diagnosis of malignant, non-teratoid medulloepithelioma. The child later underwent superficial parotidectomy and received an additional round of chemotherapy. There has been no evidence of recurrence for 9 years. Conclusions and importance: There is no standard treatment for metastatic intraocular medulloepithelioma. The neoadjuvant chemotherapy regimen used in our patient led to regression of the extrascleral extension of the tumor, allowing for enucleation rather than a more disfiguring exenteration, as well as likely improving his prognosis. We believe that it is reasonable to consider neoadjuvant chemotherapy for patients with extrascleral and/or metastatic medulloepithelioma. Keywords: Medulloepithelioma, Enucleation, Chemotherapy, Pediatric, Metastases

Purpose: To describe a case of disseminated cryptococcal meningitis with multifocal choroiditis and provide optical coherence tomography (OCT) findings correlated with described histopathology in a patient with advanced acquired immunodeficiency syndrome (AIDS). Observations: The patient was a 54-year-old man with AIDS who presented with dyspnea and headache followed by acute vision loss. OCT demonstrated a lesion with a small area of fluid that was limited by a more prominent and irregular external limiting membrane with underlying nodular choroidal thickening, mild RPE disorganization, and hyperreflectivity of the overlying photoreceptor layer. Patient was found to have disseminated cryptococcal infection and passed away despite aggressive therapy. Autopsy was performed including bilateral enucleation and a Cryptococcus lesion was confirmed on histopathology. Conclusion and importance: This case highlights the clinical, imaging, and histopathologic findings of cryptococcal choroiditis and provides a review of the updated treatment recommendations for disseminated infection in a patient with advanced AIDS. Although currently fundoscopy has proven most useful in directing the diagnostic algorithm in choroiditis in the setting of advanced immunosuppression, OCT may provide insight into the spread of Cryptococcus within the eye. Keywords: Cryptococcus neoformans, Cryptococcal choroiditis, Meningitis, HIV, AIDS, Clinicopathologic correlation

Purpose: Cotton Wool Spots (CWS) are a commonly described retinal finding in the posterior segment associated with an extensive number of systemic diseases. The appearance of a CWS in the setting of glaucoma has rarely been reported and has not been correlated with pathology to localized loss of the nerve fiber layer previously. In this case report, we augment a previous report of an 18 year old female with a diagnosis of low grade ciliary body melanoma. This patient experienced eventual mechanical angle closure with a CWS appearing in the posterior pole in the setting of acute elevation of intraocular pressure (IOP). This eye underwent enucleation and pathology evaluation. Observations: Fundus photography documented a CWS in the posterior segment during a period of acute elevation in IOP. Subsequently the eye was enucleated due to pain from refractory angle closure glaucoma secondary to low grade iris-ciliary body ring melanoma. The specific site of the prior CWS was studied with 1μ Epon retinal step sections stained with a novel AgNO3 solution. Light microscopy demonstrated a retinal nerve fiber layer scar and inner nuclear layer collapse in the prior location of the CWS. Light microscopy and transmission electron microscopy shortly after enucleation had demonstrated temporal quadrant laminar optic nerve (ON) retrograde axonal transport block. Conclusions and Importance: Although not commonly associated with glaucoma, CWS can present in the setting of acute elevations of IOP and may be associated with loss of nerve fiber layer. This loss of nerve fiber layer can confound the ability to judge glaucoma progression based on nerve fiber layer thickness via optical coherence tomography and changes in disc contours. Patient care may benefit from care provider's awareness of this possible phenomenon in the setting of angle closure. Keywords: Cotton wool spots, Secondary angle closure glaucoma, Optic nerve, Retinal nerve fiber layer, Inner nuclear layer, Optical coherence tomography

Summary: GADD34, a stress-induced regulatory subunit of the phosphatase PP1, is known to function in hyperosmotic stress through its well-known role in the integrated stress response (ISR) pathway. Adaptation to hyperosmotic stress is important for the health of corneal epithelial cells exposed to changes in extracellular osmolarity, with maladaptation leading to dry eye syndrome. This adaptation includes induction of SNAT2, an endoplasmic reticulum (ER)-Golgi-processed protein, which helps to reverse the stress-induced loss of cell volume and promote homeostasis through amino acid uptake. Here, we show that GADD34 promotes the processing of proteins synthesized on the ER during hyperosmotic stress independent of its action in the ISR. We show that GADD34/PP1 phosphatase activity reverses hyperosmotic-stress-induced Golgi fragmentation and is important for cis- to trans-Golgi trafficking of SNAT2, thereby promoting SNAT2 plasma membrane localization and function. These results suggest that GADD34 is a protective molecule for ocular diseases such as dry eye syndrome. : Here, Krokowski et al. show that GADD34/PP1 protects the microtubule network, prevents Golgi fragmentation, and preserves protein trafficking independent of its action in the integrated stress response (ISR). In osmoadaptation, GADD34 facilitates trans-Golgi-mediated processing of the endoplasmic reticulum (ER)-synthesized amino acid transporter SNAT2, which in turn increases amino acid uptake. Keywords: SNAT2, GADD34, hyperosmotic stress, amino acid transport, Golgi fragmentation, ISR

Purpose: To report two cases of patients with late extrusion following uneventful implantation of intrastromal corneal ring segments (ICRS) for myopia. Observations: Two patients with previously implanted ICRS for low myopia presented with spontaneous onset of extrusion of their ICRS, one at 7 years post-operatively and the other at 17 and 20 years. Both cases underwent explantation and maintained excellent best-corrected visual acuity. These cases represent the longest reported intervals between implantation of the ICRS and subsequent extrusion. Conclusions and importance: Late extrusion can occur many years following implantation of ICRS, even in eyes without pre-existing thinning or ectasia. The technique for explantation described herein can result in favorable clinical outcomes in such cases. These cases demonstrate the importance of long-term follow up of eyes that have undergone ICRS implantation.

Purpose: To describe the clinical course of a patient with persistent subretinal fluid (SRF) after primary scleral buckle surgery for a rhegmatogenous retinal detachment (RRD) repair who was subsequently treated with oral eplerenone for resolution of SRF. Observations: A 34 year-old-male presented with a large bullous macula-involving RRD of unknown duration and underwent primary scleral buckle and retinotomy for drainage of subretinal fluid (SRF). His post-operative course was characterized by persistent macular SRF for 1.5 years with poor vision largely unchanged from his pre-operative presentation. Patient declined additional surgical treatment and opted for conservative management. Given such persistent SRF, the patient was trialed on a course of oral eplerenone 50 mg po bid. After only one month on this therapy, a marked decline in SRF was noted with near complete resolution after two months. Conclusions and Importance: To our knowledge, this is the first report of its kind to show the effectivity of oral eplerenone treatment in the reduction of SRF following retinal detachment surgery. Keywords: Subretinal fluid, Retinal detachment, Central serous retinopathy, Eplerenone, Retinal pigment epithelium, Scleral buckling

Purpose: To report a case of severe bilateral descemetoceles in a patient with alpha-1 antitrypsin (A1AT) deficiency during intensive care unit hospitalization. Observations: A 42-year-old male presented with sub-acute bilateral vision loss during an intensive care unit hospitalization following liver and kidney transplantations. On exam, this patient's best-corrected visual acuity was 20/80 in both eyes. There were bilateral descemetoceles inferotemporally in both eyes with overlying epithelial defects and dense surrounding punctate epithelial staining. The patient was initially treated with gatifloxacin drops and frequent lubricating ointment. Given the concern for impending perforation, cyanoacrylate glue with bandage contact lens was applied to both eyes. His best corrected visual acuity remained unchanged in the right eye and improved to 20/30 in the left eye. Upon medical stabilization, anterior lamellar graft was performed in the right eye, with plans for the same treatment in the left eye in the future. Conclusions: As A1AT is found in the tear film and is believed to play a role in regulating protease activity in the cornea, we hypothesize that this patient's A1AT deficiency exacerbated the progression of corneal ulceration leading to severe descemetocele formation. Keywords: Descemetocele, Alpha-1 antitrypsin deficiency, Corneal patch graft, Corneal tectonic graft, Anterior lamellar keratoplasty

Objective The pathophysiology of Chronic Tic Disorders (CTDs), including Tourette Syndrome, remains poorly understood. The goal of this study was to compare neural activity and connectivity during a voluntary movement (VM) paradigm that involved cued eye blinks among children with and without CTDs. Using the precise temporal resolution of electroencephalography (EEG), we used the timing and location of cortical source resolved spectral power activation and connectivity to map component processes such as visual attention, cue detection, blink regulation and response monitoring. We hypothesized that neural activation and connectivity during the cued eye blink paradigm would be significantly different in regions typically associated with effortful control of eye blinks, such as frontal, premotor, parietal, and occipital cortices between children with and without CTD. Method Participants were 40 children (23 with CTD, 17 age-matched Healthy Control [HC]), between the ages of 8–12 (mean age = 9.5) years old. All participants underwent phenotypic assessment including diagnostic interviews, behavior rating scales and 128-channel EEG recording. Upon presentation of a cue every 3 s, children were instructed to make an exaggerated blink. Results Behaviorally, the groups did not differ in blink number, latency, or ERP amplitude. Within source resolved clusters located in left dorsolateral prefrontal cortex, posterior cingulate, and supplemental motor area, children with CTD exhibited higher gamma band spectral power relative to controls. In addition, significant diagnostic group differences in theta, alpha, and beta band power in inferior parietal cortex emerged. Spectral power differences were significantly associated with clinical characteristics such as tic severity and premonitory urge strength. After calculating dipole density for 76 anatomical regions, the CTD and HC groups had 70% overlap of top regions with the highest dipole density, suggesting that similar cortical networks were used across groups to carry out the VM. The CTD group exhibited significant information flow increase and dysregulation relative to the HC group, particularly from occipital to frontal regions. Conclusion Children with CTD exhibit abnormally high levels of neural activation and dysregulated connectivity among networks used for regulation and effortful control of voluntary eye blinks., Highlights • First cortical source level EEG study on brain activity and connectivity in CTD. • Children with CTD exhibit aberrant levels of neural activation and connectivity. • Neural activation was significantly associated with tic severity and premonitory urge.

Purpose To report atypical presentation of neuronal ceroid lipofuscinoses type 8 (CLN8) to the eye clinic and review clinical features of CLN8. Observations Detailed eye exam by slit lamp exam, indirect ophthalmoscopy, fundus photography, optical coherence tomography, visual fields and electroretinogram (ERG). Molecular genetic testing using Next Generation Sequencing panel (NGS) and array Comparative Genomic Hybridization (aCGH). The siblings in this study presented to the eye clinic with retinitis pigmentosa and cystoid macular edema, and a history of seizures but no severe neurocognitive deficits or regression. Genetic testing identified a c.200C > T (p.A67V) variant in the CLN8 gene and a deletion encompassing the entire gene. Electron microscopy of lymphocytes revealed fingerprint inclusions in both siblings. Conclusions and Importance: Pathogenic variants in CLN8 account for the retinitis pigmentosa and seizures in our patients however, currently, they do not have regression or neurocognitive decline. The presentation of NCL can be very diverse and it is important for ophthalmologists to consider this in the differential diagnosis of retinal disorders with seizures or other neurological features. Molecular genetic testing of multiple genes causing isolated and syndromic eye disorders using NGS panels and aCGH along with additional complementary testing may often be required to arrive at a definitive diagnosis.

Retinal degeneration (RD) affects millions of people and is a major cause of ocular impairment and blindness. With a wide range of mutations and conditions leading to degeneration, targeting downstream processes is necessary for developing effective treatments. Ceramide and sphingosine-1-phosphate, a pair of bioactive sphingolipids, are involved in apoptosis and its prevention, respectively. Apoptotic cell death is a potential driver of RD, and in order to understand the mechanism of degeneration and potential treatments, we studied rhodopsin mutant RD model, P23H-1 rats. Investigating this genetic model of human RD allows us to investigate the association of sphingolipid metabolites with the degeneration of the retina in P23H-1 rats and the effects of a specific modulator of sphingolipid metabolism, FTY720. We found that P23H-1 rat retinas had altered sphingolipid profiles that, when treated with FTY720, were rebalanced closer to normal levels. FTY720-treated rats also showed protection from RD compared with their vehicle-treated littermates. Based on these data, we conclude that sphingolipid dysregulation plays a secondary role in retinal cell death, which may be common to many forms of RDs, and that the U.S. Food and Drug Administration-approved drug FTY720 or related compounds that modulate sphingolipid metabolism could potentially delay the cell death.

Purpose To describe an atypical case of chronic central serous chorioretinopathy (CSCR). Methods A 58-year-old man with longstanding, bilateral visual impairment was self-referred for a second opinion. Results Findings by direct ophthalmoscopy, optical coherence tomography, fluorescein angiography, and fundus autofluorescence (FAF) were suggestive of atypical, chronic CSCR. Treatment with oral anti-mineralocorticoids resulted in moderate improvement, and photodynamic therapy (PDT) had minimal effect. Conclusion Chronic CSCR may lack cardinal features of CSCR. Once retinal degenerative changes ensue, current treatments may not be effective in improving anatomical and visual outcomes in patients with chronic CSCR.

While tissue form and function is highly dependent upon tissue-specific collagen composition and organization, little is known of the mechanisms controlling the bundling of collagen fibrils into fibers and larger structural designs that lead to the formation of bones, tendons and other tissues. Using the cornea as a model system, our previous 3 dimensional mapping of collagen fiber organization has demonstrated that macrostructural organization of collagen fibers involving interweaving, branching and anastomosing plays a critical role in controlling mechanical stiffness, corneal shape and refractive power. In this work, the cellular and mechanical mechanisms regulating critical events in the assembly of collagen macrostructure are analysed in the developing chicken cornea. We elucidated the temporal events leading to adult corneal structure and determined the effects of intraocular pressure (IOP) on the organization of the collagen macrostructure. Our findings indicate that the complex adult collagen organization begins to appear on embryonic day 10 (E10) after deposition of the primary stroma and full invasion of keratocytes. Importantly, organizational changes in keratocytes appearing at E9 preceded and predicted later changes in collagen organization. Corneal collagen organization remained unaffected when the development of IOP was blocked at E4. These findings support a primary role for keratocytes in controlling stromal organization, mechanical stiffness and corneal shape that are not regulated by the IOP. Our findings also suggest that the avian cornea represents an excellent experimental model for elucidating key regulatory steps and mechanisms controlling the collagen fiber organization that is critical to determining tissue form and function.Statement of significanceThis work by using an ex ovo model system, begins to investigate the potential mechanisms controlling collagen fibril macrostructure. In particular, this work highlights a convergent role for the corneal keratocytes in organizing the complex collagen macrostructure, necessary to support high visual acuity. Our data supports that the intraocular pressure does not influence collagen fibril macrostructure and suggest that the avian cornea represents an excellent experimental model for elucidating key regulatory steps and mechanisms controlling the collagen fiber organization that is critical to determining tissue form and function. Clearly understanding the cellular and molecular mechanisms that underlie collagen fibril macrostructure will be highly beneficial for future tissue engineering and regenerative medicine applications.

This paper reviews our current understanding of age-related meibomian gland dysfunction (MGD) and the role of the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ), in the regulation of meibomian gland function, meibocyte differentiation and lipid synthesis. The studies suggest that PPARγ is a master regulator of meibocyte differentiation and function, whose expression and nuclear signaling coupled with meibocyte renewal is altered during aging, potentially leading to atrophy of the meibomian gland as seen in clinical MGD. Study of meibomian gland stem cells also suggest that there is a limited number of precursor meibocytes that provide progeny to the acini, that may be susceptible to exhaustion as occurs during aging and other environmental factors. Further study of pathways regulating PPARγ expression and function as well as meibocyte stem cell maintenance may provide clues to establishing cellular and molecular mechanisms underlying MGD and the development of novel therapeutic strategies to treating this disease.

Purpose: To report on a case of uveitis and scleritis resulting as an immune-mediated side effect of cancer immunotherapy with nivolumab and cabiralizumab. Observations: Bilateral anterior nongranulomatous anterior uveitis and bilateral diffuse anterior and posterior scleritis occurred following the use of combination cancer immunotherapy. The uveitis and scleritis resolved following temporary discontinuation of nivolumab and cabiralizumab as well as systemic prednisone. Conclusions and importance: Ophthalmologists should be aware of the possibility of acute ocular inflammation developing with cancer immunotherapy. Systemic corticosteroids play a first-line role in managing such immune-mediated side effects. Keywords: Uveitis, Scleritis, Cancer immunotherapy, Side effects, Nivolumab, Cabiralizumab

Purpose To describe a case of suprachoroidal hemorrhage that occurred during femtosecond laser assisted cataract surgery (FLACS). Observations A 67-year-old woman with high myopia underwent FLACS. Following two unsuccessful attempts at docking due to interface air bubbles, the third attempt was successful. Laser treatment and cataract surgery proceeded uneventfully until intraocular lens (IOL) implantation. While positioning the IOL within the capsular bag, the anterior chamber began to shallow, intraocular pressure became high by palpation, and the optic of the IOL prolapsed partially out of the bag. A segmental suprachoroidal hemorrhage was identified in the superior peripheral retina by intraoperative indirect ophthalmoscopy. Following an hour of waiting in the recovery room, the anterior chamber deepened and the intraocular pressure was low enough to position the IOL centrally within the bag. Her subsequent postoperative course was uneventful. Conclusions and Importance To our knowledge, this is the first report of suprachoroidal hemorrhage during FLACS. We speculate that repeated sudden drops in intraocular pressure associated with multiple undockings triggered the suprachoroidal hemorrhage in this case.

Proton beam radiotherapy of uveal melanoma can be administered as primary treatment, as salvage therapy for recurrent tumor, and as neoadjuvant therapy prior to surgical resection. The physical properties of proton beams make it possible to deliver high-doses of radiation to the tumor with relative sparing of adjacent tissues. This form of therapy is effective for a wider range of uveal melanoma than any other modality, providing exceptionally-high rates of local tumor control. This is particularly the case with diffuse iris melanomas, many of which are unresectable. The chances of survival, ocular conservation, visual preservation and avoidance of iatrogenic morbidity depend greatly on the tumor size, location and extent. When treating any side-effects and/or complications, it is helpful to consider whether these are the result of collateral damage or persistence of the irradiated tumor (‘toxic tumor syndrome’).